Prolonged acceptance of concordant and discordant xenografts with combined CD40 and CD28 pathway blockade

Background. The prompt and vigorous immune response to xenogenic tissue remains a significant barrier to clinical xenotransplantation, Simultaneous blockade of the CD28 and CD40 costimulatory pathways has been shown to dramatically inhibit the immune response to alloantigen. Methods. In this study, we investigated the ability of simultaneous blockade of the CD28 and CD40 pathways to inhibit the immune response to xenoantigen in the rat-to-mouse and pig-to-mouse models. Results. Simultaneous blockade of the CD28 and CD40 pathways produced marked inhibition of the cellular response to xenoantigen in vivo and produced long-term acceptance of xenogeneic cardiac and skin grafts (rat-to-mouse), and markedly suppressed an evoked antibody response to xenoantigen, In addition, this strategy significantly prolonged the survival of pig skin on recipient mice. Conclusions. Long-term hyporesponsiveness to xenoantigen across both a concordant and discordant species barrier, measured by the stringent criterion of skin grafting, can be achieved using a noncytoablative treatment regimen.